Stabilization of amines by tartrazine and bisulfite



United States Patent Otitice This invention relatesrto the stabilization of aqueous solutions 'of aromatic amines, particularly sympathomi- J metic amines.

,Sympathominetic amines are'oiten sold as dilute aqueous solutions for application to the mucous membranes. Some of the more importantof these sympathor'nimetic amines are subject to oxidative degradation due to the influence of metal ions, heat, aeration, and light. VUnless stabilized in some manner, these solutions turn dark and `throw down heavy precipitate in amatter of a few weeks under 'room conditions. Usually it is recommended that the solution be discarded if it shows these signs of deterioration. f

Sodium meta-bisuliite has proven to be the best of the anti-oxidants as a stabilizing agent for these solutions. Concentrations of from 0.1 to 0.2 percent are eiiective stabilizers but even these amounts of sodium meta-bisulte f are not entirely adequate. There is, therefore, a definite need for improved means of stabilizing' aqueous solutions of sympathomimetic amines.

We have discovered that small amounts, 0.05 `to 0.2 percent by weight of FD and C Yellow No. Certified Dye, also known as tartrazine, is an effective stabilizer for the sympathomimetic amines alone or in combination with the usual amounts of 'sodium meta-bisulte.

To illustrate the invention in greater particularity, reference may be made to several series of experiments.

A 2 percent solution of l-phenylephrine hydrochlororide in distilled water was prepared. One hundred milliliters of the solution was` placed in a clear glass bottle which was tightly stoppered with a glass stopper and placed 'on a bench in the laboratory and maintained at room temperature for several months while exposed to normal sunlight. To another 100 milliliters solution of l-phenylephrine hydrochloride was added 0.2 percent sodium meta-bisulte. A third 100 milliliters aliquot of the l-phenylephrine hydrochloride solution was mixed with l0 milliliters of a 0.1 percent solution of tartrazine. A four-th solution was prepared with 0.2 percent sodium meta-bisulte and milliliters of 0.1 percent solution of tartrazine. All solutions were-placed in glass stoppered, clear glass bottles and placed in the sunlight. These bottles were examined from time `to time with the results shown in the following table.

As will be seen from the above results, the solution of unstabilized 1-phenylephrine commenced to turn color and threw out a precipitate within thirty-nine days. The solu- Y of deterioration.

`cipitateV at seventy-one 3,169,92 Patented Fel). 9, 1965 2 tion stabilized with sodium meta-bisultite turned purple but no precipitate had commenced to form on the thirtyninth day. The solution stabilized with the tartrazine Vhad developed only a slight darkening of color and no precipitate had formed. The solution stabilized with both sodium meta-bisulte and tartrazine was stable with no evidence of color darkening or precipitation.

On the seventy-first day the solution stabilized with the sodium meta-bisulite had a very dark purple color and a copious precipitate had formed. The solutions stabilized with tartrazine had a purple color but no precipitate had formed. The solution stabilized with both tartrazine and sodium meta-bisulte showed no 'evidence These results` show that tartrazine is a better stabilizer for l-phenylephrine than is sodium metafbisuliite and that a combination of sodium meta-bisulte and tartrazine'is better yet.V

Similarly, a series of experiments was run with the exposure being at 45 C. This series of experiments 'revealed that sodium meta-bisulte is more eiiective as a stabilizer for l-phenylephrine at 45 C. then it is at room temperature. Experiments also showed :that tartrazine was effective as a stabilizer at this temperature but to a lesser degree, and that the combination of sodium metabisullite and tartrazine also had a good stabilizing effect.

In still another series of experiments, the solutions were aerated for two hours and then placed in the sunlight. The control discolored and developed a precipitate in thirty-nine days. A solution protected with tartrazine darkened slightly in color but gave no precipitate even after seventy-one days.- The solution stabilized by sodium Imeta-bisulte had a Very darli color and had a heavy predays. When both tartrazine and sodiumrneta-bisulte were used as the stabilizing agents, there was only slight darkening at the end of seventy-one days and no precipitate had formed.

ln a similar series of experiments -in which the sympathomimetic amine was isoproterenol hydrochloride,

milliliter aliquots of a solution of 0.2 percent isoprotere-` nol hydrochloride in distilled water were prepared and exposed to sunlight as described above. The same amounts of sodium meta-bisulte and tartrazine were used as stabilizing agents. he results oi this series of experiments are shown in the following table.

As will be seen from the foregoing, tartrazine is a goodV stabilizer for isoproterenol hydrochloride and can be used effectively with sodium meta-bisulte.

In a third series of experiments, solutions of 0;5 percent ephedrine sulfate were prepared and tested by the same procedures. These solutions of 0.5 percent ephedrine sulfate proved to be fairly stable with the exception of the solution stabilized with 0.2 percent sodiummeta-bisuliite placed in sunlight which turned yellow. The solutions containing tartrazine remained stable.

The hydrogen ion concentrations of solutions of isoproterenol hydrochloride and l-phenylephrine hydrochloride stabilized with tartrazine were also studied. There were no significant changes in the pH of any of the solutions over a period of seventy-tive days.

The stabilizing action of tartrazine was also studied in the presence of small amounts of ferrie iron. Solutions 5 of 2 percent l-phenylephrine were prepared and ferrie chloride was added to bring the iron content to 10 parts per million. These solutions were then treated with sodium meta-bisultite, tartrazine, and combinations of these two stabilizing agents. The results are shown in the foll0 lowing table.

Table III Days Exposure Sunlight, Room Temperature Solution l-phenylepbrine HC1, Stable. Brown. Darker Dark brown 2.0%; 10 p.p.m. FeHt. ppt. heavy ppt. 2() 1-phenylephrine HC1, do do do Do.

2.0%; Na Meta-bisultite, 0.2%; l0 ppm. y Fe+++. l 1-plienylephrine HC1, do do.... Sl. darker, Brown ppt'.

1.8%; Tartrazine, no ppt. 0.009%; 10 p.p.1n. Fe+++. l-phonylephrine HC1, do. Stable.- Sl. Brown, Do.

1.8%; Tartrazine, noppt.

0.009%; Na Metabisulte, 0.2%; 10 p.p.m. Fe+++.

Other FD and C dyes including some of those having a yellow color were found to have little or no stabilizing action. Tartrazine may be used in the above amounts withother conventional stabilizers such as sodium metabisuliite, usually with an improved result. The aqueous solutions of the sympathomimetic amines will contain varying amounts of the amine depending upon its potency but will usually be in the range from 0.1 to 2.5 percent by weight. Other therapeutic agents which might be administered in aqueous solution, along with the sympathomimetic amines, may also be included in the solution.

What is claimed is:

1. A dilute aqueous solution containing 0.1 to 2.5 percent .by weight of a sympathomimetic amine of the group consisting of isoproterenol and 1-phenylephrine containing 0.02 to 0.2 percentl by weight of tartrazine.

2. A dilute aqueous solution containing 0.1 to 2.5 percent by weight of a sympathomimetic amine of the group consisting of isproterenol and l-phenylephrine containing 0.02 to 0.2 percent by weight of tartrazine and 0.1 to 0.2 percent'by weight of sodium meta-bisuliite.

3. An aqueous solution containing 0.1 to 2.5 percent by weight of isoproterenol stabilized with 0.02 to 0.2 percent by weight of tartrazine.

4. An aqueous solution containing 0.1 to 2.5 percent by weight of l-phenylephrine stabilized with 0.02 to 0.2 percent by weight of tartrazine.

References Cited bythe Examiner l JULIAN S. LEVITT, Primary Examiner.

F. CACCIAPAGLIA, JR., Examiner. 

1. A DILUTE AQUEOUS SOLUTION CONTAINING 0.1 TO 2.5 PERCENT BY WEIGHT OF A SYMPATHOMINETIC AMINE OF THE GROUP CONSISTING OF ISOPROTERENOL AND 1-PHENYLEPHRINE CONTAINING 0.02 T/ 0.2 PERCENT BY WEIGHT OF TARTRAZINE. 